Correlation of Asymmetric Dimethylarginine with Cardiovascular Disease in Prediabetes

INTRODUCTION

Diabetes, which is defined as a fasting blood glucose level (FBGL) of greater than 6.9 mmol/L¹ is associated with extensive organ dysfunction including diabetic retinopathy, kidney disease, and CVD, gastrointestinal disturbance, sexual dysfunction, and diabetic neuropathy.^2,3 The fatal macrovascular complications account for the majority of deaths among patients with diabetes.⁴ Risk of CVD is already increasing in prediabetes patients, i.e., impaired glucose tolerance (IGT) patients who are defined as having FBGL of 5.6–6.9 mmol/L. Some studies represent that IFG is not just a precursor of diabetes, but an individual risk factor for death. The incidence of prediabetes is increasing globally to probably more than 400 million cases in 2030 and, if untreated, will progress to diabetes and the associated complications.⁵

Endothelial dysfunction was indicated as a major cardiovascular risk factor in various trials.³ Endothelial dysfunction is defined as a decrease in bioavailability of NO°, which inhibits the adhesion and aggregation of platelets, vascular smooth muscle cell proliferation, and LDL oxidation, and adhesion of monocytes and leukocytes to the endothelium.⁴ Asymmetric dimethylarginine is essentially a competitive inhibitor of eNOS. Asymmetric dimethylarginine regulates the production rate of NO°. Asymmetric dimethylarginine is degraded by enzyme dimethylarginine dimethyaminohydrolase (DDAH) plasma ADMA concentration has been shown to increase during the course of diseases associated with endothelial dysfunction such as diabetes mellitus, peripheral artery disease, hypertension, and CVD.^6–10

Cardiovascular disease is a large account fraction of morbidity and mortality in type II diabetes.¹¹ Most of the studies were done on ADMA. Risk factors for CVD were clinically clear in diabetes mellitus, but it is not clear whether increased concentrations of ADMA are present in patients with IGT. In our view, there are hardly any studies available in Indian population regarding these biomarkers in prediabetes. The aim of present study was to evaluate serum ADMA level in prediabetes and type II diabetes patients and find the correlation with other variables.

MATERIALS AND METHODS

This study was done in the Department of Biochemistry, People’s College of Medical Science and Research Center (PCMS and RC), Centre for Scientific Research and Development (CSRD), People’s University, Bhopal. This is a cross-sectional descriptive study includes 250 type II diabetes patients, 265 prediabetes persons, and 290 controls during the period June 2017 to April 2019. Written informed consent was taken from all participants after applying inclusion and exclusion criteria. Sociodemographic data were collected by a self-designed questionnaire.

RESULTS

A total of 815 subjects participated, and out of these 255 were type II diabetes patients, 270 were prediabetes, and 290 were controls in the present study.

The level of ADMA in prediabetes was 0.55 ± 0.11 and type II diabetes was 0.70 ± 0.14 compared with controls 0.41 ± 0.14. p value was <0.05, which was significant (Table 2 and Fig. 1). Mean score of cholesterol in prediabetes was 243.34 ± 20.03 and type II diabetes was 311.92 ± 60.86 compared with controls (170.81 ± 22.34). p value was <0.001, which was significant. Mean score of triglyceride in prediabetes was 169.89 ± 14.33 and type II diabetes was 191.32 ± 40.96 compared with controls (91.11 ± 16.59). p value was <0.001, which was significant. Mean score of HDL in prediabetes was 31.10 ± 4.33 and type II diabetes was 27.97 ± 4.96 compared with controls (42.19 ± 5.82). p value was <0.001, which was significant. Mean score of LDL in prediabetes was 172.09 ± 20.03 and type II diabetes was 236.96 ± 56.27 compared with controls (109.06 ± 18.61). p value was <0.001, which was significant. Mean score of VLDL in prediabetes was 36.07 ± 7.04 and type II diabetes was 47.56 ± 10.45 compared with controls (19.04 ± 4.83). p value was <0.001, which was significant. Mean score of TG/HDL in prediabetes was 5.58 ± 1.00 and type II diabetes was 7.23 ± 2.22 compared with controls (2.19 ± 0.49). p value was <0.05, which was significant. Mean score of LDL/HDL in prediabetes was 5.74 ± 1.08 and type II diabetes was 8.94 ± 3.43 compared with controls (2.61 ± 0.56). p value was <0.001, which was significant (Table 2).

DISCUSSION

It is well recognized that type II diabetes and its metabolic derangements such as hyperinsulinemia, hyperglycemia, dyslipidemia, and increased oxidative stress are associated with NO-mediated endothelial dysfunction.¹⁹ In contrast, endothelial dysfunction may lead to attenuated glucose uptake in insulin-sensitive tissues, hyperglycemia, and ultimately to the development of insulin resistance and type II diabetes.^20,21 Furthermore, impaired NO° bioavailability plays a pivotal role in the regulation of glucose-stressed endothelial progenitor cell dysfunction in type II diabetes, and antioxidant treatment with superoxide dismutase may restore their function.²² ADMA, an endogenous competitive inhibitor of NO° synthase, is known to impair NO° bioavailability and endothelial function.²³ Overexpression of DDAH, the enzyme responsible for the elimination of ADMA in human, may lead to reduced plasma ADMA level and enhance insulin sensitivity.²⁴ In human studies, insulin resistance is related to plasma ADMA concentration, impaired ability of enzyme DDAH, and treatment with rosiglitazone, and weight reduction enhances insulin sensitivity and significantly lowers plasma ADMA level.^25,26 Plasma ADMA level has been reported to be correlated with treadmill stress test-derived outcome parameters²⁷ and asymptomatic carotid atherosclerosis.²⁸ In prediabetic subjects, elevated ADMA was strongly associated with increased arterial stiffness, which is a well-established predictor of cardiovascular outcomes.²⁹ Hyperglycemia is associated with endothelial dysfunction both in vivo³⁰ and in vitro;³¹ therefore, endothelial dysfunction is an early feature in the development of vascular complications in people with diabetes. These findings suggest that the elevated ADMA in diabetes could contribute to accelerated atherosclerosis in this population.³²

Studies comparing ADMA levels of prediabetic subjects with healthy people are inconclusive. Although some studies report increased ADMA levels in prediabetes.³³ Eliana et al. report no significant difference between groups. Associations between increased levels of ADMA and many cardiovascular risk factors such as age, hypertension, diabetes, insulin resistance, hypercholesterolemia, hypertriglyceridemia, smoking, and BMI have been accepted.³⁴ In our study, we found that ADMA levels were elevated in prediabetes and type II diabetes compared with healthy controls.

In our study, plasma ADMA levels were significantly increased in the prediabetes and type II diabetes compared with the control group. We suggest that increased ADMA levels could contribute to impaired endothelial function in prediabetic stage. Recent studies have indicated that LDL particle concentrations, and specifically LDL levels, are predictors of coronary events, and it is an independent coronary disease risk factor.³⁵ At the molecular level, high LDL-C levels induce endothelial cell dysfunction with subsequent decreased NO° bioavailability due to impaired l-arginine transport and metabolism and eNOS uncoupling. Peroxynitrite, the major uncoupling byproduct of eNOS, has been reported to directly damage elastin.³⁶ Studies show that subjects with the metabolic syndrome and/or DM have higher sLDL levels than controls.^37,38 In our study, we find a significant difference in serum lipid profile levels between the groups.

CONCLUSION

The current study shows increased ADMA levels can indicate the risk of CVD in prediabetic stage and type II diabetes. The evaluation of the ADMA levels may improve the early diagnosis of CVD in prediabetes patients. Along with routine investigations, an early detection of ADMA will help the clinicians to plan line of treatment in a better manner. Well-balanced nutrition, patient education, diet counseling, and supplementation therapies for high risk group of diabetic patients are strongly recommended.

The outcome of our study is to know the role of ADMA in prediabetes and diabetes in clinical manifestations of the disease, which ultimately helps us in better management of the patient. This study will help us develop the criteria for preventive measures of the disease using biochemical markers in predicting the disease.

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